The broad, long-range objective of these studies is to define the molecular basis of neuronal dysfunction in Alzheimer's disease. We have developed transgenic mice expressing the amyloid precursor protein (APP) for animal studies of Alzheimer's disease (Hsiao et al., 1996). These mice simulate several behavioral and neuropathological features of Alzheimer's disease. We propose to delineate the molecular domains of APP responsible for these behavioral and neuropathological abnormalities. Because hundreds of researchers around the world have begun using these mice as a model for Alzheimer's disease, we feel compelled to dispel even the slightest doubts about the reproducibility of the phenotypic traits we observed. Therefore, we shall embark upon producing another line of mice over-expressing mutant human APP exhibiting both age-related behavioral and pathological abnormalities simulating Alzheimer's disease in humans in AIM #1. In AIM #2 we shall examine the role of alphabeta in producing age-related neural dysfunction in the brain. By comparing the behavioral and neuropathological profiles of transgenic mice expressing wild-type APP and APP lacking the alphabeta domain to transgenic mice over-expressing mutant APP we shall determine which biological and behavioral abnormalities are due to alphabeta accumulation and which can be attributed solely to APP over-expression. Elucidating the role of alphabeta in functional brain abnormalities in Alzheimer's disease is a critical and timely question that can now be approached by studying neural dysfunction in transgenic APP mice. We shall also distinguish between the more and less amyloidogenic forms of alphabeta, alphabeta40 and alphabeta42(43), by comparing, by comparing behavioral and neuropathological profiles of transgenic mice expressing APP with the Swedish (KM670/671 NL) and London (V717I) mutations. In Aim #3 we shall determine whether the KPI domain in APP influences the onset and rate of amyloid formation. In different laboratories APP isoforms with or without KPI domains have both been used to generate transgenic mice developing amyloid plaques (Games et al., 1995; Hsiao et al., 1996; Sturchler-Pierrat et al., 1997). Although the topographical and morphological features of the amyloid deposits are remarkably similar in these mice, the presence or absence of the KPI domain in the APP transgene might account for differences in the chronological appearance and amount of alpha/beta deposition. Whether the KPI domain alone can explain these differences remains unresolved because of slight potential variations in APP levels and differences in promoters used to drive APP expression in the two lines of mice. To answer this question we shall compare alphabeta levels, temporal patterns and extent of alphabeta deposits, as well as profiles of behavioral impairment in transgenic mice, expressing mutated APP with and without the KPI domain driven at comparable levels by the identical promoter.